The present study shows that initial measurement of RI in patients with various nephropathies at time of renal biopsy is clinically relevant for several reasons. We show that RI is associated with renal function and pulse pressure, a surrogate marker of arterial stiffness. More importantly, RI is associated with severe interstitial fibrosis and arteriosclerosis and eGFR decline. Previous studies reported either the association of RI with interstitial fibrosis, tubulo-interstitial lesions [9–12, 25], or vascular lesions [9–11] or renal outcome in CKD [9, 11, 13, 15, 16]. To our knowledge, none of these studies simultaneously evaluated the association of RI with the main chronic renal histological lesions and with renal function outcome. Furthermore, the most relevant threshold of RI for clinical practice was still debated. Here, the cut-off value of 0.65 was the most discriminant for severe arteriosclerosis, extended fibrosis and renal function decline.
In this study, we analyzed the association of RI with pathological changes and renal function outcome in an unselected population of 58 patients with various nephropathies and renal function alterations. In order to be closer to clinical practice, our inclusion criteria differ from other studies which were done in specific renal diseases [12, 25]. Our results emphasize the general predictive value of RI in CKD patients independently of the type of nephropathy. Secondly, only well-defined chronic renal lesions as interstitial fibrosis, percentage of sclerotic glomeruli, arteriosclerosis lesions were taken into account in our study. These criteria differ from previous studies which used combined scores as tubulo-interstitial injury or interstitial fibrosis/tubular atrophy, which could reflect acute kidney injury [9–12]. Despite a relative small population of CKD patients, we found a significant association of RI with severe renal lesions and renal function decline, consistently with previous studies [9–16, 20].
As previous authors, we found a positive correlation between RI and age [10, 26–29] and in a lesser extent with pulse pressure [26, 30–33]. Prior studies reported an association between RI and other markers of arterial stiffness as pulse wave velocity [31, 34] and ankle-brachial blood pressure index . In our study, RI was not associated with systolic nor with diastolic blood pressure despite its relationship with pulse pressure. This suggests that the elevation of RI rather reflects the vascular consequences of hypertension than hypertension itself. An alternative explanation is the lack of power of our study. Nevertheless, this result was demonstrated by previous authors who showed that RI is a marker of target organ damage in essential hypertension [30, 32, 34, 36, 37] as left ventricular hypertrophy, carotid and coronary atherosclerosis. Other studies demonstrated that high RI was also associated with systemic atherosclerosis in diabetic patients [31, 38] and renal transplant recipients . Moreover, Pearce et al. recently showed that elevated renal RI is predictive of cardiovascular events in the elderly .
The elevation of RI with severe arteriosclerosis may account for its association with cardiovascular risk. As previous authors [9, 25], we actually found an association between RI and renal arteriosclerosis. It is interesting to note that only patients with severe intima thickening exhibited high RI. Nor hyaline arteriolar deposits nor moderate intima thickening were associated with increased RI. This could be due to the lack of power of our study. Nevertheless, it could also suggest that the presence of moderate vascular lesions is not sufficient to induce an elevation of RI and that these alterations must be important enough to reduce artery lumen, raise arterial stiffness and vascular resistance, and consequently generate an increase in RI. Overall, these findings suggest that high RI reflects severe renal arteriosclerosis and maybe systemic arteriosclerosis.
Our study also questioned the correlation of RI with renal fibrosis. We did not find any relationship between RI and glomerulosclerosis. Moreover, RI was significantly lower in case of isolated glomerular involvement, i.e. without any vascular and/or tubulo-interstitial damage. This result corroborates previous findings of Platt et al.. Only one among three previous studies found a significant association between glomerulosclerosis and RI . This correlation was weak in a second study  and not significant in a multivariate analysis in the third one . Altogether, these findings suggest that glomerulosclerosis does not influence the value of RI.
On the other hand, as other authors, we found an association between RI value and the extension of interstitial fibrosis [9, 11, 12, 25] and the severity of renal impairment [13, 26, 40–44]. Median percentage of interstitial fibrosis was six fold higher in patients with RI exceeding 0.65. As arteriosclerosis, interstitial fibrosis appears as an important determinant of RI. Three hypotheses can be drawn about the physiopathological mechanisms involved in elevation of RI with the progression of CKD: i) decrease in arterial compliance and increase in vascular resistance because of renal arteriosclerosis, ii) elevation of pressure exerted by interstitial fibrosis on adjacent vessels, iii) vasoconstriction secondary to the hypoxia induced by the previous phenomena and by the loss of capillaries associated with renal fibrosis. These mechanisms are probably combined and our results do not allow us to precise which one contributes the most to the elevation of RI.
In the second part of our study, we found that high RI was independently associated with accelerated renal function decline. Sugiura et al. reported similar result in a larger cohort of 311 CKD patients followed-up for two years. Such results were also found by other authors in CKD [11, 14–17], essential hypertension  and renal transplantation [8, 45]. Our results extend previous findings to a population of patients with various nephropathies. The concomitant association of RI with interstitial fibrosis and arteriosclerosis which are known to be major determinants of the progression of CKD  may explain its prognosis value.
Finally, we attempted to define the most relevant threshold of RI in clinical practice. Consistently with the first findings of Sugiura et al. , we found that 0.65 was the most accurate threshold to detect extent interstitial fibrosis, but also severe arteriosclerosis. Nevertheless, more recently, Sugiura et al. suggested that 0.70 threshold was better than 0.65 cut-off to predict renal function decline . In contrast, we found by ROC curves analysis that RI ≥ 0.65 has the best sensitivity (77%) and specificity (86%) to discriminate renal function decline. This discrepancy may be explained by the different definitions of renal function decline used in the two studies. Using the criteria of at least 10 mL/min/ 1.73 m2/year, Sugiura et al. may have selected more severe patients. In cohort studies, mean slope of eGFR decline is less than 5 mL/min/ 1.73 m2 in most CKD patients [2, 19–23]. A decrease of 5 mL/min/ 1.73 m2/year appears to be closer to clinical practice and more helpful to detect a larger of number patients at high risk of accelerated CKD progression.
Our study has several limits. We mostly included glomerulonephritis and few vascular and tubulo-interstitial diseases. Because of the weak proportion of chronic vascular and tubulo-interstitial diseases, we can wonder whether our results could apply to those nephropathies. Nevertheless, several previous studies found an association between high RI and poor renal outcome in essential hypertension and chronic tubulo-interstitial nephropathies [13, 14, 17, 34, 37]. The main limit of our study is the non exhaustive collection of renal function data. However, our results corroborate those of several previous studies [9, 11, 13, 15, 16].